Safety assessment of basiliximab using real-world adverse event data from the FDA Adverse Event Reporting System Database: A retrospective observational study

This study analyzed adverse drug events (ADEs) associated with basiliximab, sourced from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, spanning the first quarter of 2004 to the fourth quarter of 2023. We collected ADE data for basiliximab from 2004 Q1 to 2023 Q4. After standardization, we employed several signal quantification methods for analysis, such as the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propensity for Neural Networks (BCPNN), and empirical bayes geometric mean (EBGM). In this analysis of 1520 ADEs reports citing basiliximab as the primary suspect, we identified 295 preferred terms across 24 system organ classifications (SOCs). The 3 most prevalent SOCs were investigated (n = 1403, ROR 2.84, PRR 2.54, IC 1.34, EBGM 2.54), infections and infestations (n = 1198, ROR 2.85, PRR 2.59, IC 1.37, EBGM 2.59), and renal and urinary disorders (n = 903, ROR 6.01, PRR 5.48, IC 2.45, EBGM 5.47). Increased blood creatinine and pyrexia were the most frequently reported adverse events (AEs) associated with basiliximab, and cytomegalovirus infection also demonstrated significant signal intensity. Notably, this study revealed some adverse reactions beyond basiliximab drug instructions, such as mitral valve calcification, diastolic dysfunction, pelvic fluid collection, testicular swelling, soft tissue necrosis, and muscle necrosis. Although basiliximab offers therapeutic benefits, it carries the risk of several adverse reactions. Clinicians should monitor patients for signs of increased serum creatinine level, fever, cytomegalovirus infection, anaphylactic shock, mitral valve calcification, diastolic dysfunction, pelvic fluid collection, testicular swelling, soft tissue necrosis, muscle necrosis, and other events during clinical use.


Introduction
Basiliximab, a chimeric monoclonal antibody, has been shown to effectively prevent early posttransplant kidney rejection, demonstrating significant advantages over placebo.[3][4] This drug is particularly beneficial in individuals with renal impairment.Its use leads to a strategic delay in the administration of calcineurin inhibitors, which are known to potentially worsen kidney damage if introduced too early in the treatment process.By allowing this delay, basiliximab ensures a safer and more controlled treatment progression, minimizing the risks associated with premature intervention. [5]asiliximab, while generally effective in preventing transplant rejection, also presents potential side effects that necessitate thorough examination and vigilance. [6]Numerous extensive literature reviews have methodically discussed these adverse effects and highlighted the importance of understanding their implications.[9] Consequently, this situation underscores the urgent need to develop and adopt more effective methods to systematically summarize and analyze these adverse reactions.Such an approach would ensure a more accurate and comprehensive understanding of the safety profile of basiliximab and contribute to better patient care and drug utilization strategies.
Pharmacovigilance plays a vital role in monitoring, evaluating, and effectively mitigating the adverse effects and issues associated with drug use, and is pivotal for ensuring patient safety and enhancing drug efficacy. [10]In the modern healthcare landscape, pharmacovigilance databases have become indispensable tools for conducting real-world postmarketing studies.These databases are instrumental in ongoing safety assessments of medications currently in public use, providing essential data that help inform regulatory decisions and clinical practice. [11]By systematically collecting and analyzing data on drugrelated issues, these databases facilitate prompt identification and proactive addressing of any concerns, significantly improving healthcare outcomes by ensuring that medications remain safe and effective for patient populations.
The FAERS database plays a crucial role in the gathering and examination of drug-related adverse drug events (ADEs).This study employed FAERS data on basiliximab to meticulously analyze its safety through various signal quantification techniques.

Data source
This study utilized the American Standard Code for Information Interchange report files from the FAERS database.

Data extraction and analysis
Redundant reports were removed, retaining only the most recent report for each unique case ID in the demographic database based on the date.Data were linked through the "primaryid" field, and reports identifying basiliximab as the primary drug associated with ADEs were selected.The study applied 4 disproportionality methods -Reporting Odds Ratio (ROR), [12] Proportional Reporting Ratio (PRR), [13] Bayesian Confidence Propensity for Neural Networks (BCPNN), [14] and empirical bayes geometric mean (EBGM) [15] -were used to detect drug ADE signals.ROR addresses the bias from limited reports on specific events, PRR offers specificity, BCPNN excels in integrating and cross-validating data from various sources, and EBGM can detect signals from rare events.This combined approach leverages the strengths of each algorithm to broaden the detection scope, validate the findings from multiple perspectives, and ensure more reliable safety signal identification.Cross-validation across algorithms helps to reduce false positives.Adjustments in thresholds and variance enabled the identification of rare adverse reactions.All methods utilize 2 × 2 contingency tables, as detailed in Table 1, with precise calculations and threshold values in Table 2. Statistical analysis was performed using R. Higher values indicated stronger signal intensity, suggesting a more significant association between the drug and adverse events (AEs).Figure 1 illustrates the precise method used to identify AEs associated with basiliximab in the FAERS database.

Signal filtering and categorization
The initial screening filtered for preferred terms (PTs) was reported 3 or more times.Using the Medical Dictionary for Regulatory Activities for PT and SOC, this study encoded and categorized signals for analysis, particularly focusing on system organ classifications (SOCs) related to AE signals.

Basic characteristics of basiliximab-related AE reports
This study extracted 20,079,906 AE reports from the FAERS database from the first quarter of 2004 to the fourth quarter of 2023.Of these, basiliximab was highlighted as the first suspect in 1520 ADEs reports (Fig. 2).These AE reports were very unevenly distributed between females and males, with only 471 reports in females and 864 in males.A major challenge in this analysis was the lack of gender information in 12.17% of the reports, which limited a comprehensive study of the relationship between gender and AEs.Where age data were available, the 18 to 65 years age group dominated, but 21.58% of the reports lacked gender information, which is a major challenge in analyzing a comprehensive study of the age-AE relationship.
The source of reporting was mainly other health professionals (39.41%) and consumers (14.28%), but physicians accounted for only 28.49%, which shows the lack of physicians reporting AEs.For Reported countries, the highest number of reports was from India (10.92%); details can be found in Figure 3.In terms of known types of clinical outcomes, hospitalization is the most common AE (31.18%), followed by death (13.93%).Further details are provided in Table 3.      5.In addition, this study ranked the top 50 PTs based on the number of reports they reported, as shown in Figure 5.In this study, adverse reactions included increased blood creatinine, pyrexia, cytomegalovirus infection, decreased hemoglobin, decreased lymphocyte count, decreased urine output, respiratory failure, increased white blood cell count, decreased platelet count, and increased neutrophil count.These monitored adverse reactions were consistent with basiliximab drug instructions.Notably, this study revealed some adverse reactions beyond basiliximab drug instructions, such as mitral valve calcification, diastolic dysfunction, pelvic fluid collection, testicular swelling, soft tissue necrosis, and muscle necrosis.

Onset time of events
Figure 6 shows the timing of basiliximab-related AE.A total of 439 AEs (68.32 %) occurred within 28 days after drug administration, of which 310 (43.30%) occurred within 1 week of drug administration.However, a subset of AEs (n = 97, 13.55%) occurred after long-term (> 2 months) treatment with basiliximab.Notably, there was a large proportion of adverse reactions (n = 117, 16.34%), and the time of occurrence was unknown.

Concomitant medication
Table 6 meticulously enumerates the most frequently used concomitant medications in conjunction with basiliximab, with a focus on those reported in AE scenarios.The enumeration highlights the top ten concomitant medications, which notably include prednisolone, with a considerable frequency of 719 instances, followed by tacrolimus (454 times) and mycophenolate mofetil (388 times).Additionally, furosemide was mentioned in 362 reports, ganciclovir in 207, sulfamethoxazole in 170, sodium bicarbonate in 154, prednisone in 150, nifedipine in 138, and albumin in 120.
Further analysis extends to the top 30 drugs, which are systematically categorized into several groups based on their therapeutic applications.These categories include immunosuppressants, such as tacrolimus, mycophenolate mofetil, prednisolone, prednisone, cyclosporine, and rituximab, which play a pivotal role in preventing organ rejection.The diuretic category includes furosemide and torsemide, which are essential for managing fluid balance.The antiviral agents listed are ganciclovir and acyclovir, which are crucial for combating viral infections in immunocompromised patients.Antibiotics include potent drugs, such as sulfamethoxazole, meropenem, and amikacin, which are integral to the prevention and treatment of bacterial infections.Moreover, the list includes categories such as electrolytes and minerals, represented by sodium bicarbonate, calcium gluconate, and albumin, which are vital for maintaining the electrolyte balance and plasma volume.Hormones and related therapeutic agents such as insulin, erythropoietin, and folic acid are crucial for metabolic regulation and anemia, respectively.Respiratory drugs, including ambroxol hydrochloride, are beneficial for managing respiratory conditions.The analgesics and antipyretics category, featuring acetaminophen and aspirin, addresses pain and fever management.
Cardiovascular medications, such as nifedipine, metoprolol tartrate, and diltiazem hydrochloride, are essential for managing blood pressure and heart rhythm disorders.The gastrointestinal drugs listed include esomeprazole magnesium, ranitidine hydrochloride, lansoprazole, and hydrotalcite, all of which help manage acid-related gastrointestinal conditions.Lastly, the vasodilators category, with drugs such as alprostadil, plays a crucial role in improving blood flow.This comprehensive categorization underscores the complex and multidimensional nature of medication management in basiliximab-treated patients.

Discussion
To our knowledge, this is the most thorough pharmacovigilance study to date on basiliximab-associated AEs using postmarketing data from the FAERS database.This study offers a precise and comprehensive description of the AEs associated with basiliximab.Real-world monitoring of medication uses and associated AEs aftermarket release is crucial for confirming safety and efficacy.By analyzing FAERS data from Q1 2004 to Q4 2023, this study not only corroborated existing safety information, but also uncovered potential new risks, providing valuable insights for clinical practice and public health policy.An in-depth analysis is as follows.
The disparity in basiliximab-associated AEs between sexes was evident, yet the substantial lack of sex data (12.17%)hindered a precise analysis of sex-specific reactions.Future efforts should prioritize the collection of sex-specific data to enhance our understanding of the adverse effects of basiliximab.The scarcity of age-related information also limits insights into AEs across different age groups, underscoring the need for more detailed age data in future research to examine age-related drug responses.The low rate of physician-reported cases (28.49%)  points to a gap in physician engagement with AE reporting; thus, increasing physician awareness and reporting is crucial.With 10.92% of reports coming from India and 10.72% reporting from the USA, further research is needed to explore the potential regional or cultural factors influencing these findings.
The most common adverse reactions monitored in this study included increased serum creatinine level, fever, cytomegalovirus infection, decreased hemoglobin level, decreased lymphocyte count, decreased urine output, respiratory failure, increased white blood cell count, decreased platelet count, and decreased neutrophil count.In addition, we also found that bacterial sepsis, fungal skin infection, abdominal abscess, subcutaneous abscess, Aspergillus infection, renal artery thrombosis, and renal atrophy only occurred in a small number of patients.The most common SOCs are investigations, infections, renal and urinary disorders, immune system disorders, general disorders, administration site conditions, injuries, poisoning and procedural complications, gastrointestinal disorders, blood and lymphatic system disorders, and respiratory, thoracic, and mediastinal disorders.These results are generally consistent with the manufacturer's labeling and clinical trials.
Research demonstrates that there are no significant disparities in infection rates between patients administered basiliximab and those administered a placebo, as documented in multiple studies. [3,4,16,17]This indicates that basiliximab, used in this context, does not increase the general risk of infections compared with standard care without active treatment.However, it is important to note that urinary tract infections continue to be frequently observed among individuals receiving basiliximab, suggesting a specific area where this medication does not reduce the infection prevalence. [3,16]In a robust study involving a large cohort of 722 renal transplant recipients, which included both individuals with and without diabetes, basiliximab demonstrated a high level of tolerability across this diverse group of patients. [18]Furthermore, detailed comparisons between basiliximab and antithymocyte globulin, another commonly used induction therapy agent, indicated that both treatments offer comparable safety outcomes.
Studies show that neither treatment significantly increases the risk of developing malignancies or infections or leads to higher mortality rates. [19,20]Notably, basiliximab is associated with a lower incidence of AEs, with only 11% of patients experiencing undesirable effects as opposed to 42% of those treated with antithymocyte globulin. [19]This significant difference highlights the advantage of basiliximab in terms of patient experience and risk management, making it a potentially more favorable option in clinical settings, where the reduction of adverse effects is a critical concern.This reinforces the role of basiliximab as a preferred agent in transplantation medicine, balancing its effectiveness with patient safety.
A focused study involving 32 kidney transplant recipients further reinforced the notion that basiliximab is well tolerated, with negligible immune reactions observed in the participants. [21]Despite its overall safe profile, there have been instances where acute hypersensitivity reactions to basiliximab, as well as to daclizumab, another immunosuppressive drug, have been reported.These reactions are rare, but serious enough to warrant attention.Nevertheless, when compared overall, the side effects of both basiliximab and daclizumab are largely similar to those observed with placebo, indicating that these reactions are exceptions rather than the rule. [4,22]The side effects associated with these immunosuppressive agents affect only a small percentage of recipients, ranging from 3% to 10%.These primarily include conditions related to dermatological issues and infections, which, while relatively minor, require monitoring and management to ensure patient safety and comfort. [4]ecent research has shown that the typical side effects associated with basiliximab are diverse and include symptoms such as chills, fever, rash, fatigue, diarrhea, nausea, headache, anorexia, leukopenia, and infections.These side effects are relatively common and are recognized as manageable within the context of treatment, although they can significantly affect patient comfort and treatment adherence. [23]n addition to these common adverse effects, this study also highlights a spectrum of rare but potentially severe side effects associated with the use of basiliximab.These include acute allergic reactions, which can manifest swiftly and intensely; anaphylaxis, a life-threatening systemic allergic reaction that requires immediate medical intervention; capillary leak syndrome, which involves a sudden leakage of fluid from the capillaries that can lead to shock; cytokine release syndrome, a severe inflammatory response that can be life-threatening; and progressive multifocal leukoencephalopathy, a rare brain infection that leads to significant neurological decline. [23]Awareness and prompt management of these severe side effects are crucial to ensure patient safety and optimize treatment outcomes.
The data observed at this time, based on the FAERS database, show that among all reported infectious diseases, there were   only 3 cases urinary tract infections, and the most common infectious disease was cytomegalovirus infection (n = 122).This reminds us that, among the adverse reactions of basiliximab, attention should be paid to the adverse reactions of infection, especially cytomegalovirus infection.
It is worth noting that no acute AEs of hypersensitivity reactions to basiliximab were observed in previous studies. [3,4,21,24,25]owever, this study found that anaphylactic shock had a high frequency and signal intensity (n = 16, ROR 4.45, PRR 4.45, IC 2.15, EBGM 4.45).This reminds us to pay attention to monitor the occurrence of anaphylactic shock when basiliximab is used.
A total of 439 AEs (68.32 %) occurred within 28 days after drug administration, of which 310 (43.30%) occurred within 1 week of drug administration.However, 97 AEs (13.55 %) occurred after long-term (>2 months) basiliximab treatment.This may be due to the latent period of the drug, or because the patient's body has strong resistance and slow metabolism, which prolongs the time required to establish the cumulative drug concentration, and the body cannot fully absorb the drug, so most adverse drug reactions occur later.Therefore, a longer follow-up period is required to observe the adverse effects of basiliximab in future clinical studies.
The described AEs and their potential mechanisms associated with basiliximab remain speculative.Confirming the exact causes requires further investigation, considering the influence of drug properties, individual variability, and preexisting conditions on AE development.Therefore, additional clinical and experimental studies are essential for a comprehensive understanding of AEs.Clinicians should closely monitor AE occurrence to manage them effectively.
Our study of the safety of basiliximab, while providing valuable insights, has limitations.First, reliance on voluntary FAERS reporting could lead to skewed data due to factors such as FDA warnings, possibly causing underreporting or inaccuracies.Second, our analysis offers a statistical perspective on potential risks without confirming the causal links between the drug and reported AEs.Incomplete patient information in some reports further complicates causality assessments, highlighting the need for additional research.Despite these challenges, this study contributes to the understanding of basiliximab-related AEs, supporting their cautious use in healthcare.Further investigation is necessary to fully decode AE mechanisms.Healthcare professionals should monitor AEs to effectively manage risks.

Conclusion
In conclusion, although this study illuminates the safety profile of basiliximab through extensive pharmacovigilance analysis, it is important to recognize its inherent limitations.Dependency on voluntary FAERS reports introduces potential biases, including underreporting and the influence of external alerts, which may skew the findings.Furthermore, the study's analytical approach, focused on signal strength, stops short of establishing causality between basiliximab and the observed AEs.Despite these challenges, our research provides valuable insights into the spectrum of AEs associated with basiliximab, enhancing our collective understanding and guiding safer clinical use.These findings underscore the necessity for ongoing vigilance in monitoring AEs and advocate for further research to elucidate the underlying mechanisms of these events.Through these efforts, we can better navigate the complexities of drug safety and optimize patient care in the evolving field of organ transplantation.

Figure 1 .
Figure 1.Flow diagram of selection of basiliximab-related AEs from the FAES database.

Figure 2 .
Figure 2. The number of AEs was reported quarterly after basiliximab marketing.

Figure 3 .
Figure 3. World distribution of adverse reactions.

Figure 5 .
Figure 5. Bar graphs show the number of top 50 AEs for basiliximab in the FAERS database.The color indicates the SOC corresponding to the PT.Abscissa indicates the number of reports.

Figure 6 .
Figure 6.Time to onset of basiliximab-related adverse AEs.

Table 1
Four grid table.

Table 4 .
3.2.2.Signals detection based on PT levels.This study applied 4 algorithms at the PT level to assess drug reactions and their alignment with screening criteria, identifying 295 PTs listed in Supplementary TableS1, Supplemental Digital Content, http://links.lww.com/MD/N491.The numbers of PT reports greater than 5 are listed in Table

Table 3
Basic information on ADEs related to basiliximab from the FAERS database.
ADEs = adverse drug events, FAERS = Food and Drug Administration Adverse Event Reporting System.

Table 4
The signal strength of ADEs of basiliximab at the SOC level in FAERS database.

Table 5
PTs reporting numbers >5 in the FAERS database.

Table 6
Top 30 concomitant medications.= confidence interval, FAERS = Food and Drug Administration Adverse Event Reporting System, PTs = preferred terms, ROR = reporting odds ratio, SOC = system organ classification. CI